Bottom Line:
We previously reported a pilot case series followed by a small, randomized, placebo-controlled phase II study, suggesting that B-cell depletion using the monoclonal anti-CD20 antibody rituximab can yield clinical benefit in ME/CFS.Clinically significant responses were seen in 18 out of 28 patients (64%) receiving rituximab maintenance treatment.The observed patterns of delayed responses and relapse after B-cell depletion and regeneration, a three times higher disease prevalence in women than in men, and a previously demonstrated increase in B-cell lymphoma risk for elderly ME/CFS patients, suggest that ME/CFS may be a variant of an autoimmune disease.

Background: Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology. We previously reported a pilot case series followed by a small, randomized, placebo-controlled phase II study, suggesting that B-cell depletion using the monoclonal anti-CD20 antibody rituximab can yield clinical benefit in ME/CFS.

Methods: In this single-center, open-label, one-armed phase II study (NCT01156909), 29 patients were included for treatment with rituximab (500 mg/m2) two infusions two weeks apart, followed by maintenance rituximab infusions after 3, 6, 10 and 15 months, and with follow-up for 36 months.

Findings: Major or moderate responses, predefined as lasting improvements in self-reported Fatigue score, were detected in 18 out of 29 patients (intention to treat). Clinically significant responses were seen in 18 out of 28 patients (64%) receiving rituximab maintenance treatment. For these 18 patients, the mean response durations within the 156 weeks study period were 105 weeks in 14 major responders, and 69 weeks in four moderate responders. At end of follow-up (36 months), 11 out of 18 responding patients were still in ongoing clinical remission. For major responders, the mean lag time from first rituximab infusion until start of clinical response was 23 weeks (range 8-66). Among the nine patients from the placebo group in the previous randomized study with no significant improvement during 12 months follow-up after saline infusions, six achieved a clinical response before 12 months after rituximab maintenance infusions in the present study. Two patients had an allergic reaction to rituximab and two had an episode of uncomplicated late-onset neutropenia. Eight patients experienced one or more transient symptom flares after rituximab infusions. There was no unexpected toxicity.

Conclusion: In a subgroup of ME/CFS patients, prolonged B-cell depletion with rituximab maintenance infusions was associated with sustained clinical responses. The observed patterns of delayed responses and relapse after B-cell depletion and regeneration, a three times higher disease prevalence in women than in men, and a previously demonstrated increase in B-cell lymphoma risk for elderly ME/CFS patients, suggest that ME/CFS may be a variant of an autoimmune disease.

pone.0129898.g002: Self-reported Fatigue scores for 28 patients receiving rituximab induction and maintenance treatment.Fatigue score was recorded every second week, always compared to baseline, as the mean of four fatigue-related symptoms (scale 0–6; 3: no change from baseline; 4, 5, 6: slight, moderate, major improvement, respectively; 2, 1, 0: slight, moderate, major worsening, respectively). Panel A shows Fatigue scores for the time intervals 0–6, 6–12, 12–18, 18–24, 24–30 and 30–36 months, with means and 95% CI for each time interval. In panel B the corresponding Fatigue scores are shown for each time interval during follow-up, divided between 18 patients with clinically significant responses, and 10 patients with either marginal response (n = 1) or no response (n = 9). Out of 10 patients with no clinically significant response, one patient withdrew from study after 12 months, and four patients after 24–26 months follow-up. Out of 18 patients with clinically significant responses, one withdrew from study after 24 months due to a diagnosis of T2N0 breast cancer, two moderate responders withdrew after 25 and 32 months, respectively, and one major responder withdrew after 32 months.

Mentions:
The self-reported Fatigue scores for the 28 patients given rituximab induction and maintenance treatment are shown in Fig 2A, with mean Fatigue scores for each six-months time interval during three years follow-up. Table 1 shows data for each of these 28 patients, including sex, age, possible preceding infection, ME/CFS disease characteristics (duration and severity), participation in previous studies, autoimmunity among first-degree relatives, number of rituximab infusions, response periods and response durations during follow-up, clinical status at end of study, and also SF-36 and Function level data at selected time points (0-15-24-36 months).

pone.0129898.g002: Self-reported Fatigue scores for 28 patients receiving rituximab induction and maintenance treatment.Fatigue score was recorded every second week, always compared to baseline, as the mean of four fatigue-related symptoms (scale 0–6; 3: no change from baseline; 4, 5, 6: slight, moderate, major improvement, respectively; 2, 1, 0: slight, moderate, major worsening, respectively). Panel A shows Fatigue scores for the time intervals 0–6, 6–12, 12–18, 18–24, 24–30 and 30–36 months, with means and 95% CI for each time interval. In panel B the corresponding Fatigue scores are shown for each time interval during follow-up, divided between 18 patients with clinically significant responses, and 10 patients with either marginal response (n = 1) or no response (n = 9). Out of 10 patients with no clinically significant response, one patient withdrew from study after 12 months, and four patients after 24–26 months follow-up. Out of 18 patients with clinically significant responses, one withdrew from study after 24 months due to a diagnosis of T2N0 breast cancer, two moderate responders withdrew after 25 and 32 months, respectively, and one major responder withdrew after 32 months.

Mentions:
The self-reported Fatigue scores for the 28 patients given rituximab induction and maintenance treatment are shown in Fig 2A, with mean Fatigue scores for each six-months time interval during three years follow-up. Table 1 shows data for each of these 28 patients, including sex, age, possible preceding infection, ME/CFS disease characteristics (duration and severity), participation in previous studies, autoimmunity among first-degree relatives, number of rituximab infusions, response periods and response durations during follow-up, clinical status at end of study, and also SF-36 and Function level data at selected time points (0-15-24-36 months).

Bottom Line:
We previously reported a pilot case series followed by a small, randomized, placebo-controlled phase II study, suggesting that B-cell depletion using the monoclonal anti-CD20 antibody rituximab can yield clinical benefit in ME/CFS.Clinically significant responses were seen in 18 out of 28 patients (64%) receiving rituximab maintenance treatment.The observed patterns of delayed responses and relapse after B-cell depletion and regeneration, a three times higher disease prevalence in women than in men, and a previously demonstrated increase in B-cell lymphoma risk for elderly ME/CFS patients, suggest that ME/CFS may be a variant of an autoimmune disease.

Background: Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology. We previously reported a pilot case series followed by a small, randomized, placebo-controlled phase II study, suggesting that B-cell depletion using the monoclonal anti-CD20 antibody rituximab can yield clinical benefit in ME/CFS.

Methods: In this single-center, open-label, one-armed phase II study (NCT01156909), 29 patients were included for treatment with rituximab (500 mg/m2) two infusions two weeks apart, followed by maintenance rituximab infusions after 3, 6, 10 and 15 months, and with follow-up for 36 months.

Findings: Major or moderate responses, predefined as lasting improvements in self-reported Fatigue score, were detected in 18 out of 29 patients (intention to treat). Clinically significant responses were seen in 18 out of 28 patients (64%) receiving rituximab maintenance treatment. For these 18 patients, the mean response durations within the 156 weeks study period were 105 weeks in 14 major responders, and 69 weeks in four moderate responders. At end of follow-up (36 months), 11 out of 18 responding patients were still in ongoing clinical remission. For major responders, the mean lag time from first rituximab infusion until start of clinical response was 23 weeks (range 8-66). Among the nine patients from the placebo group in the previous randomized study with no significant improvement during 12 months follow-up after saline infusions, six achieved a clinical response before 12 months after rituximab maintenance infusions in the present study. Two patients had an allergic reaction to rituximab and two had an episode of uncomplicated late-onset neutropenia. Eight patients experienced one or more transient symptom flares after rituximab infusions. There was no unexpected toxicity.

Conclusion: In a subgroup of ME/CFS patients, prolonged B-cell depletion with rituximab maintenance infusions was associated with sustained clinical responses. The observed patterns of delayed responses and relapse after B-cell depletion and regeneration, a three times higher disease prevalence in women than in men, and a previously demonstrated increase in B-cell lymphoma risk for elderly ME/CFS patients, suggest that ME/CFS may be a variant of an autoimmune disease.